News Beyond Our Pages
Authors: Marc E. Rothenberg, Jean Bousquet
Journal: Journal of Allergy and Clinical Immunology (2022)

Su et al (Cell 2022;185:881-95.e20; https://doi.org/10.1016/j.cell.2022.01.014) clarified the underpinnings of post-acute sequelae of COVID-19 (PASC) through extensive multi-omic analyses of a longitudinal cohort of over 300 subjects. PASC was associated with type 2 diabetes mellitus, autoantibody levels, latent reactivation of Epstein-Barr virus, and degree of SARS-CoV-2 viremia at the time of initial infection. Interestingly, even subclinical baseline autoantibody production was found to significantly reduce anti-SARS-CoV-2 antibody production. Additionally, PASC patients with gastrointestinal symptoms exhibited a unique expansion of cytotoxic T cells during recovery. Finally, subjects were stratified into 4 distinct immune endotypes. Collectively, these findings have identified long COVID-associated biological and immunologic factors, the majority of which are detectable at the time of initial diagnosis, that may inform future interventional trials. Image attribution Wikimedia by users Alissa Eckert, MS and Dan Higgins, MAM, Public domain, via Wikimedia Commons: https://commons.wikimedia.org/wiki/Commons:Reusing_content_outside_WikimediaThe majority of which are detectable at the time of initial diagnosis The majority of which are detectable at the time of initial diagnosis Type 2 immune responses involved coordinated actions of group 2 innate lymphoid cells (ILC2s) and TH2 cells at mucosal barriers and perivascular adventitial cuffs. Cautivo et al (Immunity 2022;55:254-71.e7; https://doi.org/10.1016/j.immuni.2021.12.014) identified that type 2 inflammation induced expansion and redistribution of ILC2s and TH2 cells to de novo parenchymal sites in both the lung and liver. Interestingly, type 1 lymphocyte-derived IFN-γ acted directly on ILC2s and TH2s to prevent parenchymal redistribution. IFN-γ restricted type 2 lymphocyte topography via several mechanisms, including blocking trafficking and inducing parenchymal ILC2 and TH2 cell death to prevent excess type 2 inflammation during concurrent type 1 and type 2 immune responses, such as in response to infection with Listeria monocytogenes. Overall, these results identify an important role of IFN-γ-producing type 1 lymphocytes in balancing mixed immune responses by limiting niche expansion of ILC2s and TH2 cells. We asked corresponding author, Ari B. Molofsky, MD, PhD, of the Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California, to comment on the study. Dr Molofsky writes, “Our work describes a crosstalk between type 1 and type 2 lymphocytes that is governed by location within tissues, whereby activated type 1 lymphocytes produce IFN-γ to restrict type 2 immunity to perivascular adventitial niches. As multiple ‘flavors’ of lymphocytic immunity are engaged during organ infection, damage, cancer, and fibrosis, our findings suggest that lymphocyte topography may be a critical and unexplored determinant that impacts tissue health and pathology.” Diny et al (J Exp Med 2022;219:e20210970; https://doi.org/10.1084/jem.20210970) identified dramatic transcriptional and functional changes in eosinophils upon trafficking from the bone marrow to the small intestine that partially depended on sensing of environmental ligands by the aryl hydrocarbon receptor (AHR). Notably, loss of AHR signaling impaired the ability of eosinophils to adhere to extracellular matrix and increased both their longevity and propensity for degranulation. Importantly, eosinophil-specific lack of AHR broadly affected intestinal immunity, including T cell compartment composition during both homeostasis and helminth infection. These findings demonstrate that AHR signaling mediates small intestine eosinophil tissue adaption and warrant further study in other immune cell populations. Image attribution Wikimedia by user ScienceWriterK, CC BY-SA 4.0 https://creativecommons.org/licenses/by-sa/4.0, via Wikimedia Commons.Eosinophil-specific lack of AHR broadly affected intestinal immunity Eosinophil-specific lack of AHR broadly affected intestinal immunity C1-esterase inhibitor-deficient hereditary angioedema (HAE-C1-INH) results from bradykinin overproduction secondary to excess activation of the kallikrein-kinin system. Craig et al (Lancet 2022;399:945-55; https://doi.org/10.1016/S0140-6736(21)02225-X) performed a placebo-controlled Phase 2 study examining the efficacy of prophylaxis with garadacimab, a mAb that targets activated factor XII to prevent subsequent activation of the kallikrein-kinin system. Both tested doses of garadacimab reduced hereditary angioedema attacks by over 90% compared to placebo. Importantly, garadacimab was well-tolerated with no serious adverse events observed. Based on these findings, further Phase 3 study of prophylactic garadacimab in patients with HAE-C1-INH is warranted.Garadacimab reduced hereditary angioedema attacks by over 90 percent Garadacimab reduced hereditary angioedema attacks by over 90 percent The steady-state function of the thymus maintains peripheral T-cell populations, and secondary immunodeficiencies can occur in response when the thymus is damaged during cancer therapies such as radiation and chemotherapy. Cosway et al (Sci Immunol 2022;7:eabn3286; https://doi.org/10.1126/sciimmunol.abn3286) examined the molecular mechanisms of thymic repair after sublethal irradiation. Type 2 cytokines released from radioresistant invariant natural killer T (NKT) cells induced eosinophil recruitment and colonization within hours under the action of the chemokine CCL11. Eosinophils were sustained through IL-5 production by group 2 innate lymphoid cells and regenerated epithelial microenvironments were able to reestablish thymopoiesis. Collectively, these results identify a novel intrathymic type 2 immune axis that promotes thymic regeneration in response to damage. We asked corresponding author Graham Anderson, BSc, PhD, of the Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom, to comment on the study. He writes, “We reveal an NKT-ILC2-Eosinophil axis that controls the recovery of thymus function following damage. The ability of the ILC2 product IL5 to boost thymus recovery may point towards new approaches to therapeutically improve immune reconstitution.”Graham AndersonView Large Image Figure ViewerDownload Hi-res image Download (PPT)News items were written by medical writer Jared Travers, MD, PhD. News items were written by medical writer Jared Travers, MD, PhD.